Gene Variants Predict Response to Breast Cancer Drugs

Scientists found genetic variations that could be used to identify women who are most likely to benefit from a certain type of breast cancer prevention drug—and who should avoid it.

Women with a high risk for developing breast cancer — for example, those with a family history of the disease or a previous tumor — can take certain medications that reduce the chance of developing breast cancer. Tamoxifen and raloxifene, 2 such drugs, are selective estrogen receptor modulators. These drugs work by blocking the effects of estrogen, a hormone that can promote the growth of breast cancer tumors.

To prevent breast cancer, at-risk women may take tamoxifen or raloxifene for 5 years. In rare cases, the drugs can cause dangerous side effects, including blood clots, strokes and endometrial cancer. Many women decide that the chance of success doesn’t outweigh the risk of side effects. If doctors could better predict a patient’s likely response to therapy, more women might benefit from this potentially life-saving strategy.

Dr. James N. Ingle of the Mayo Clinic led an international team — including scientists at the RIKEN Center for Genomic Medicine in Tokyo — to search for genetic markers that might predict treatment failure. They used data from long-running breast cancer prevention trials that involved more than 33,000 high-risk women. The scientists looked for genetic differences between women who developed breast cancer while on treatment and those who remained disease-free. They analyzed 500,000 genetic variations (single-nucleotide polymorphisms, or SNPs) scattered across the genome. The study was supported in part by NIH’s National Cancer Institute (NCI) and National Institute of General Medical Sciences (NIGMS).

In the July 2013 issue of Cancer Discovery, the team reported that 2 SNPs — one in a gene called ZNF423 and the other near a gene called CTSO — tended to differ between women who developed breast cancer while on treatment and those who remained cancer-free. Women who had only the beneficial versions of both SNPs were about 6 times less likely to develop breast cancer than women who had only the high-risk versions.

Neither ZNF423 nor CTSO had previously been associated with breast cancer or the response to these drugs. Further experiments revealed that both genes are involved in estrogen-induced expression of the BRCA1 protein, which is known to affect breast cancer risk.

“Our study reveals the first known genetic factors that can help predict which high-risk women should be offered breast cancer prevention treatment and which women should be spared any unnecessary expense and risk from taking these medications,” Ingle says. “We also discovered new information about how the drugs tamoxifen and raloxifene work to prevent breast cancer.”